PDBsum entry 5m2b

Hydrolase/hydrolase inhibitor

PDB id: 5m2b

Contents

Protein chains

250 a.a.

244 a.a.

240 a.a.

235 a.a.

231 a.a.

243 a.a.

241 a.a.

226 a.a.

204 a.a.

195 a.a.

211 a.a.

222 a.a.

233 a.a.

196 a.a.

Ligands

7DX ×2

Metals

_CL ×4

_MG ×7

Waters ×446

PDB id:

5m2b

Name:

Hydrolase/hydrolase inhibitor

Title:

Yeast 20s proteasome with human beta5i (1-138) and human beta6 (97- 111; 118-133) in complex with thiazole based inhibitor ro19

Structure:

Proteasome subunit alpha type-2. Chain: a, o. Synonym: macropain subunit y7,multicatalytic endopeptidase complex subunit y7,proteasome component y7,proteinase ysce subunit 7. Proteasome subunit alpha type-3. Chain: b, p. Synonym: macropain subunit y13,multicatalytic endopeptidase complex subunit y13,proteasome component y13,proteinase ysce subunit 13. Proteasome subunit alpha type-4.

Source:

Saccharomyces cerevisiae (strain atcc 204508 / s288c). Baker's yeast. Organism_taxid: 559292. Strain: atcc 204508 / s288c. Homo sapiens, saccharomyces cerevisiae s288c. Human. Organism_taxid: 9606, 559292. Gene: psmb8, lmp7, psmb5i, ring10, y2, pre2, doa3, prg1, ypr103w,

Resolution:

2.70Å R-factor: 0.201 R-free: 0.218

Authors:

M.Groll

Key ref:

H.Cui et al. (2017). Structural Elucidation of a Nonpeptidic Inhibitor Specific for the Human Immunoproteasome. Chembiochem, 18, 523-526. PubMed id: 28098422 DOI: 10.1002/cbic.201700021

Date:

12-Oct-16 Release date: 25-Jan-17

Protein chains

P23639  (PSA2_YEAST) -  Proteasome subunit alpha type-2 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 250 a.a.

Struc: 250 a.a.

Protein chains

P23638  (PSA3_YEAST) -  Proteasome subunit alpha type-3 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 258 a.a.

Struc: 244 a.a.

Protein chains

P40303  (PSA4_YEAST) -  Proteasome subunit alpha type-4 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 254 a.a.

Struc: 240 a.a.

Protein chains

P32379  (PSA5_YEAST) -  Proteasome subunit alpha type-5 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 260 a.a.

Struc: 235 a.a.

Protein chains

P40302  (PSA6_YEAST) -  Proteasome subunit alpha type-6 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 234 a.a.

Struc: 231 a.a.

Protein chains

P21242  (PSA7_YEAST) -  Probable proteasome subunit alpha type-7 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 288 a.a.

Struc: 243 a.a.

Protein chains

P21243  (PSA1_YEAST) -  Proteasome subunit alpha type-1 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 252 a.a.

Struc: 241 a.a.

Protein chains

P25043  (PSB2_YEAST) -  Proteasome subunit beta type-2 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 261 a.a.

Struc: 226 a.a.

Protein chains

P25451  (PSB3_YEAST) -  Proteasome subunit beta type-3 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 205 a.a.

Struc: 204 a.a.

Protein chains

P22141  (PSB4_YEAST) -  Proteasome subunit beta type-4 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 198 a.a.

Struc: 195 a.a.

Protein chains

P28062  (PSB8_HUMAN) -  Proteasome subunit beta type-8 from Homo sapiens

Seq: 276 a.a.

Struc: 211 a.a.*

Protein chains

P30656  (PSB5_YEAST) -  Proteasome subunit beta type-5 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 287 a.a.

Struc: 211 a.a.*

Protein chains

P20618  (PSB1_HUMAN) -  Proteasome subunit beta type-1 from Homo sapiens

Seq: 241 a.a.

Struc: 222 a.a.*

Protein chains

P23724  (PSB6_YEAST) -  Proteasome subunit beta type-6 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 241 a.a.

Struc: 222 a.a.*

Protein chains

P30657  (PSB7_YEAST) -  Proteasome subunit beta type-7 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 266 a.a.

Struc: 233 a.a.

Protein chains

P38624  (PSB1_YEAST) -  Proteasome subunit beta type-1 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 215 a.a.

Struc: 196 a.a.

* PDB and UniProt seqs differ at 200 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, X, Y, Z, a, b: E.C.3.4.25.1 - proteasome endopeptidase complex.
• Reaction: Cleavage at peptide bonds with very broad specificity.

DOI no: 10.1002/cbic.201700021

Chembiochem 18:523-526 (2017)

PubMed id: 28098422

Structural Elucidation of a Nonpeptidic Inhibitor Specific for the Human Immunoproteasome.

H.Cui, R.Baur, C.Le Chapelain, C.Dubiella, W.Heinemeyer, E.M.Huber, M.Groll.

ABSTRACT

Selective inhibition of the immunoproteasome is a promising approach towards the development of immunomodulatory drugs. Recently, a class of substituted thiazole compounds that combine a nonpeptidic scaffold with the absence of an electrophile was reported in a patent. Here, we investigated the mode of action of the lead compound by using a sophisticated chimeric yeast model of the human immunoproteasome for structural studies. The inhibitor adopts a unique orientation perpendicular to the β5i substrate-binding channel. Distinct interactions between the inhibitor and the subpockets of the human immunoproteasome account for its isotype selectivity.